RESUMO
It is widely accepted that more needs to be done to bring new, safe, and efficacious drugs to the market. Cardiovascular toxicity detected both in early drug discovery as well as in the clinic, is a major contributor to the high failure rate of new molecules. The growth of translational safety offers a promising approach to improve the probability of success for new molecules. Here we describe a cross-company initiative to determine the concordance between the conscious telemetered dog and phase I outcome for 3 cardiovascular parameters. The data indicate that, in the context of the methods applied in this analysis, the ability to detect compounds that affect the corrected QT interval (QTc) was good within the 10-30x exposure range but the predictive or detective value for heart rate and diastolic blood pressure was poor. These findings may highlight opportunities to refine both the animal and the clinical study designs, as well as refocusing the assessment of value of dog cardiovascular assessments beyond phase 1. This investigation has also highlighted key considerations for cross-company data sharing and presents a unique learning opportunity to improve future translational projects.
Assuntos
Ensaios Clínicos Fase I como Assunto/estatística & dados numéricos , Avaliação Pré-Clínica de Medicamentos/estatística & dados numéricos , Indústria Farmacêutica/normas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Pesquisa Translacional Biomédica/métodos , Animais , Pressão Sanguínea/efeitos dos fármacos , Cardiotoxicidade , Ensaios Clínicos Fase I como Assunto/métodos , Ensaios Clínicos Fase I como Assunto/normas , Cães , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/normas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/fisiopatologia , Eletrocardiografia , Voluntários Saudáveis , Frequência Cardíaca/efeitos dos fármacos , Humanos , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Telemetria , Pesquisa Translacional Biomédica/normas , Pesquisa Translacional Biomédica/estatística & dados numéricosRESUMO
INTRODUCTION: Preclinical assessment of the heart rate corrected QT interval (QTc) is an important component of the cardiovascular safety evaluation in drug discovery. Here we aimed to quantify the translational relationship between QTc prolongation and shortening in the conscious telemetered dog and humans by a retrospective pharmacokinetic-pharmacodynamic (PKPD) analysis. METHODS: QTc effects of 2 proprietary compounds and 2 reference drugs (moxifloxacin and dofetilide) were quantified in conscious dogs and healthy volunteers via a linear and Emax pharmacokinetic-pharmacodynamic models. The translational relationship was quantified by correlating the QTc response from dog and human at matching free drug concentrations. RESULTS: A consistent translational relationship was found at low delta-QTc intervals indicating that a QTc change of 2.5-8 ms in dog would correspond to a 10 ms change in human. DISCUSSION: The translational relationship developed here can be used to predict the QTc liability in human using preclinical dog data. It could therefore help protect the health of human volunteers, for example by appropriate clinical study design and dose selection, as well as improve future decision-making and help reduce compound attrition due to changes in QT interval.
Assuntos
Compostos Aza/farmacocinética , Síndrome do QT Longo/induzido quimicamente , Modelos Biológicos , Fenetilaminas/farmacocinética , Quinolinas/farmacocinética , Sulfonamidas/farmacocinética , Adulto , Animais , Compostos Aza/toxicidade , Compostos Azabicíclicos/farmacocinética , Compostos Azabicíclicos/toxicidade , Benzimidazóis/farmacocinética , Benzimidazóis/toxicidade , Carbamatos/farmacocinética , Carbamatos/toxicidade , Ensaios Clínicos Fase I como Assunto , Cães , Método Duplo-Cego , Avaliação Pré-Clínica de Medicamentos/métodos , Eletrocardiografia , Feminino , Fluoroquinolonas , Humanos , Masculino , Pessoa de Meia-Idade , Moxifloxacina , Fenetilaminas/toxicidade , Quinolinas/toxicidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Especificidade da Espécie , Sulfonamidas/toxicidade , Telemetria , Pesquisa Translacional Biomédica , Adulto JovemRESUMO
In this preliminary study UPLC-ICP-MS has been utilized to profile a range of different bio-fluids and tissue extracts for sulfur and phosphorus-containing metabolites. Particular attention has been given to the livers, plasma and urine from lean and obese Zucker rats, with a view to differentiating between them based solely on their respective sulfur or phosphorus profiles and/or their total sulfur and phosphorus content. In addition, bile and tumour extracts have been analysed to observe the nature of their profiles. To the best of our knowledge this is the first time ICP-MS has been used in a non-targeted metabonomic study. Results have shown lower limits of quantification for sulfur and phosphorus methods of 0.25 and 0.15 ng on column with CVs of 14.7% and 10.9% respectively. Total phosphorus analysis of the Zucker rat aqueous liver extracts, plasma and urine has shown the pattern of phosphorus concentrations to be statistically significantly different in the lean and obese Zucker rats. Chromatographic separation of the Zucker rat organic liver extracts and plasma allowed further differentiation between the lean and obese rats using their phosphorus profiles alone. In conclusion, this preliminary study has shown the potential of UPLC-ICP-MS to quantitatively discriminate between different species biofluids, fluids and tissues based solely on their phosphorus or sulfur concentrations and/or metabolomes.